Peripheral neuropathy is the most common neurological complication associated with HIV-1 infection, affecting over one-third of HIV-infected individuals with AIDS. In addition, studies have found a high prevalence of HIV sensory neuropathy in HIV-infected patients receiving highly active antiretroviral therapy. Although HIV-induced damage to the peripheral nervous system is a frequent and debilitating consequence of infection, its pathogenesis is incompletely understood. To study this disease, we established an SIV/macaque model in which over 90 percent of animals develop PNS changes closely resembling those seen in HIV-infected individuals with distal sensory neuropathy, including inflammation of the dorsal root ganglia with abundant replication of SIV in macrophages and neuronal loss, sural nerve inflammation, and reduction in the number of epidermal nerve fibers in the feet. This constitutes the first primate model of HIV-induced peripheral neuropathy. Our goal is to use this model to dissect the pathogenesis and the underlying molecular basis of HIV-induced PNS disease. Our hypothesis is that HIV first replicates in macrophages within the DRG in the PNS, inducing a cascade of viral and macrophage-produced neurotoxic products, which activate p38 MAPK signaling pathways in somatosensory neurons that trigger sodium channel dysregulation. To address this hypothesis, we have proposed three Aims: Aim 1 is to determine whether SIV-induced PNS disease is initiated by replication of gangliotropic viruses that trigger production of neurotoxic viral and macrophage gene products in the DRG of SIV- infected macaques and to determine whether neurovirulent viruses remain latent in the DRG when no active virus replication is detected in DRG. Aim 2 is to determine the order in which components of the pain pathway, including DRG, sensory fibers in peripheral nerve, and epidermal nerve fibers are damaged in DSP. Aim 3 is to determine whether a) SIV-induced PNS disease is associated with altered conductive properties of unmyelinated C fibers and alterations in expression levels and distribution of sodium channels in DRG neurons, and b) to determine whether active replication of SIV in DRG macrophages induces activation of p38 in DRG neurons thereby modulating the expression and location of sodium channels in DRG neurons. The goal of these comprehensive, integrated studies of HIV sensory neuropathy in our novel SIV primate model is to advance the understanding of HIV-SN pathogenesis to foster new therapeutic approaches. [unreadable] [unreadable] [unreadable]